pages 348-355 (vasculitis)

pages 355-356 (disorders of blood vessel hyper reactivity, veins and lymphatics)

Blood Vessels:

Vascular disease develops through two principle mechanisms:

o Narrowing or complete obstruction of vessel lumina, occurring either
progressively (such as atherosclerosis) or acutely (by thrombosis or embolism).
o Weakening of vessel walls, causing dilation and/or rupture.

Structure and Function of Blood Vessels:

All blood vessels consist of a tube with a luminal lining of endothelial cells surrounded by
varying amounts of smooth muscle cells and ECM; varies based on functional needs:
o Pulsatile flow and higher blood pressures: arterial walls thicker than veins and
invested with reinforcing layers of smooth muscle cells.
Atherosclerosis occurs, mainly in larger, muscular arteries, while
hypertension affects small arterioles.
o Arteriesarterioles; ratio of wall thickness to lumen diameter increases to allow
more precise regulation of intravascular pressures.
o Veinsdistensible thin-walled vessels with high capacitance.
Vessel wallsintima, media, adventitiamost apparent in larger vessels (eg. Arteries)
o Intimaendothelial cell monolayer on basement membrane with minimal
underlying ECM; separated from media by dense elastic membrane called
internal elastic lamina.
o Mediasmooth muscle cells and ECM surrounded by loose connective tissue,
nerve fibers, and smaller vessels of the adventitia.
An external elastic lamina is present in some arteries and defines the
transition between media and adventitia.
Diffusion of oxygen and nutrients from the lumen is adequate to sustain thin-walled
vessels and the innermost smooth muscle cells of all vessels.
In large and medium-sized vessels, small arterioles within the adventitiavasa vasorum
supply the outer half to two thirds of the media.
Vascular organization:

Arteries are divided into three types based on size and structure:
o Large elastic arterieselastic fibers alternate with smooth muscle cells
throughout the media; expands during systole; storing some of the energy of
each cardiac contraction; and recoils during diastole to propel blood distally. With
age, lose elasticity, vessels stiff, transmit high arterial pressures to distal organs
or dilated and tortuous (ectatic) conduits prone to rupture.
Aorta, arch vessels, iliac and pulmonary arteries
o Medium-sized muscular arteriesmedia composed of smooth muscle cells, with
elastin limited to the internal and external elastic lamina. Medial smooth muscle
cells are circularly or spirally arranged around lumen, regional blood flow is
regulated by smooth muscle cell contraction (vasoconstriction) and relaxation
 (vasodilation) controlled by autonomic nervous system and local metabolic
factors (acidosis).
Coronary and renal arteries
o Small arteries (2mm or less diameter) and arterioles (20-100 micrometers in
diameter) that lie within the connective tissue of organsmedia is mostly
composed of smooth muscle cells. Arterioles are where blood resistance is
regulated. As pressures drop during passage through arterioles, the velocity of
blood flow is sharply reduced, and flow becomes steady rather than pulsatile.
Resistance to fluid flow is inversely proportional to the fourth power of the
diameter (halving the diameter increases resistance 16 fold), small
changes in arteriole lumen size have profound effects on blood pressure.
Capillaries have lumen diameters the size of red cells (7-8 micrometers)lined by
endothelial cells and partially surrounded by smooth muscle cell-like cells called
pericytes.
o Capillary beds have a large total cross-sectional area and low rate of blood flow.
o Thin walls and slow flow, capillaries are suited to the rapid exchange of diffusible
substances between blood and tissue.
o Capillary network of most tissues is rich, diffusion of oxygen and nutrients is not
efficient beyond 100 micrometers; metabolically active tissues (heart) have the
highest capillary density.
o Veins receive blood from capillary beds as post-capillary venules, which
anastomose to form collecting venules and progressively larger veins.
Vascular leakage (edema) and leukocyte emigration from inflammation
occurs in postcapillary venules.
Veins have larger diameters, larger lumina, and thinner walls with less distinct layers, all
adaptations to the low pressures found on the venous side of the circulation.
o Veinsmore prone to dilation, external compression, and penetration by tumors
or inflammatory processes.
o Veins in which blood flows against gravity, backflow prevented by valves.
Venous system has huge capacitance and normally contains two-thirds of the blood.
Lymphaticsthin-walled, endothelium-lined channels that drain fluid from interstitium of
tissues, returns to blood via thoracic duct.
o Contains mononuclear inflammatory cells and proteins
o Deliver interstitial fluid to lymph nodesenable monitoring of peripheral tissues
for infection.
o Can also disseminate disease by transporting microbes or tumor cells to distant
sites.
Endothelial cells:

Endotheliumcontinuous sheet of cells lining entire vascular tree that regulates blood
and blood vessel functions.
o Resting endothelial cellsmaintain nonthrombogenic blood-tissue interface,
modulate inflammation, and affect growth of other cell types (eg. Smooth muscle
cells).
o Influence vasoreactivity of underlying smooth muscle cells by producing relaxing
factors (NO) and contracting factors (endothelin).
 o Interendothelial junctionsimpermeable, but open under hemodynamic stress
(high BP) and vasoactive agents (histamine release), flooding adjacent tissues
with electrolytes and protein.
o Vacuolar transcytosispermits movement of large amounts of solutes across
intact endothelium.
o Active participants in the egress of leukocytes during inflammatory cell
recruitment.
Endothelial cells show phenotypic variabilitydepends on anatomic site and adaptations
to local environmental cues; distinct transcriptional programs and behaviors.
o Hepatocyte cords/Renal glomerulifenestrations in endothelial cells are
specializations that facilitate filtration.
o CNSendothelial cells with astrocytes collaborate to generate impermeable
blood brain barrier.
Normal nonthrombogenic endothelial cell-lining maintenance requires laminar flow,
growth factors (vascular endothelial growth factor), and firm adhesion to underlying
basement membrane)
o Trauma or other injuries that denude vessel walls of endothelial cells
thrombosis and vasoconstriction.
Endothelial cells also respond to various physiologic and pathologic stimuli by
modulating their constitutive (usual) functions and by expressing inducible (new)
propertiesendothelial activation.
o Inducersbaterial products, inflammatory cytokines, hemodynamic stresses,
lipid products (atherosclerosis), advanced glycation end products (important in
diabetic vascular injury), viruses, complement, and various metabolic insults
(hypoxia).
Activated endothelial cells undergo shape changes, express adhesion
molecules, and produce cytokines, chemokines, growth factors, pro/anti-
coagulant factors, etcall intended to respond to original stimulus.

Property/Function Mediators/Products

Maintenance of
permeability barrier

Elaboration of anti- Prostacyclin

coagulant, anti-thrombotic, Thrombomodulin
and fibrinolytic regulators

Heparin-like molecules
Plasminogen activator

Elaboration of Von Willebrand factor

prothrombotic molecules Tissue factor

Plasminogen activator inhibitor

Production of extracellular Collagen, proteoglycans

matrix

Modulation of blood flow Vasoconstrictors: endothelin, ACE

and vascular reactivity Vasodilators: NO, prostacyclin

Regulation of inflammation IL-1, IL-6, chemokines
and immunity Adhesion molecules: VCAM-1, ICAM, E-selectin, P-selectin

Histocompatibility antigens

Regulation of cell growth Growth stimulators: PDGF, CSF, FGF

Growth inhibitors: heparin, TGF-

Oxidation of LDL
 Some responses are rapid (minutes), reversible, and independent of new protein
synthesis (endothelial contraction induced by histamines)
Others involve alterations in gene and protein expression, and may take days to develop
or abate.
Exposure to inducers in high amounts or for sustained periodsendothelial dysfunction
impaired endothelium-dependent vasodilation, hypercoagulable states, and increased
oxygen free radical production.
o Initiate thrombosis, promote atherosclerosis, or contribute to formation of
vascular lesions of hypertension and diabetes.

Vascular Smooth Muscle Cells:

Smooth muscle cellsparticipate in both normal vascular repair and pathologic

processes such as atherosclerosis.
When stimulated by factorssmooth muscle cells can proliferate; upregulate ECM
collagen, elastin, and proteoglycan production; and elaborate GFs and cytokines.
Migratory and proliferative activities regulated byplatelet-derived growth factor,
endothelin, thrombin, fibroblast growth factors, and inflammatory mediators, such as
IFN-gamma and interleukin-1.
Factors that maintain smooth muscle cells in quiescent stateheparan sulfate, NO, and
transforming growth factor-alpha.
Smooth muscles can also mediate vasoconstriction or vasodilation that occurs in
response to physio/pharmacologic stimuli.
Vasculitis:

Vasculitisvessel wall inflammation

o Classified based on vessel size, role of immune complexes, presence of
specific auto-Abs, granuloma formation, tissue tropism, etc.
o Clinical manifestations are protean but depend on the specific vascular
bed affected.
o Signs and symptoms of systemic inflammation, such as fever, myalgia,
arthralgia, malaise.
Several forms of vasculitis have predilection for large vessels (large or
medium-sized muscular arteries), but most affect small vessels (arterioles,
capillaries, and venules).
Two most common pathogenic mechanisms of vasculitis are immune-
mediated inflammation and direct vascular invasion by infectious pathogens.
o Infections can also indirectly precipitate immune-mediated vasculitis
(by generating immune-complexes or triggering cross reactivity)
o Critical to distinguish between infectious and immunologic
mechanisms because immunosuppressive therapy is appropriate for
immune-mediated vasculitis but exacerbates infectious vasculitis.
o Physical and chemical injury (radiation, mechanical trauma, toxins) can
also cause vasculitis.
Vascular injury arises from complement activation or the recruitment of Fc-
receptor-bearing cells.
Non-infectious Vasculitis:

Main immunologic mechanisms underlying non-infectious vasculitis:

o Immune complex deposition
o Anti-neutrophil cytoplasmic Abs
o Anti-endothelial cell Abs
o Autoreactive T cells
Immune Complex-Associated Vasculitis:
o Seen in immunological disorder, such as SLE (eg. DNA/anti-DNA
complexes) that are associated with autoantibody production.
o Lesions resemble Arthus phenomenon and serum sickness, contain
readily identifiable antibody and complement.
Diagnostic challenge; rarely is specific antigen responsible for
immune complex formation known.
While immune complexes are detected in blood sometimes, not
clear whether the pathogenic antigen-Ab complexes are
deposited from circulation or form in situ.
In many suspected cases, even antigen-Ab deposits scarce
because immune complexes have been degraded by time of
biopsy.
Immune complex deposition implicated in:
o Drug hypersensitivity vasculitis
Drugs (penicillin) act as haptens by binding to host proteins;
other agents are themselves foreign proteins (streptokinase)
Ab directed against drug-modified proteins or foreign molecules
result in immune complex formation.
Clinical manifestationsmild and self-limiting/severe or fatal;
skin lesions most common
Discontinuing offending agentresolution
o Vasculitis secondary to infections
Ab to microbial constituents can form immune complexes that
circulate and deposit in vascular lesions.
Eg. 30% polyarteritis nodosa patients, vasculitis
attributable to immune complexes composed of hepatitis
B surface antigen and anti-HBsAg Ab.
Anti-Neutrophil Cytoplasmic Antibodies:

Many with vasculitis have circulating Abs that react with neutrophil
cytoplasmic antigens, ANCAs.
Heterogenous group of auto-Abs directed against constituents (enzymes) of
neutrophil primary granules, monocyte lysosomes, and endothelial cells.
Useful diagnostic marketstiters mirror clinical severity, rise in titers after
quiescence is predictive of disease recurrence.
o Suggests pathogenic role for antibodies
Two most important ANCAs:
o Antiproteinase-3 (PR3-ANC)
 PR3neutrophil azurophilic granule constituent that shares
homology with many microbial peptides, explaining generation
of PR3-ANCAs; associated with Wegener granulomatosis.
o Anti-myeloperoxidase (MPO-ANCA)
MPO is a lysosomal granule constituent involved in oxygen free
radical generation
MPO-ANCAs are induced by therapeutic agents
(propylthiouracil); associated with microscopic polyangiitis and
Churg-Strauss syndrome.
ANCAs can directly activate neutrophils, stimulating release of reactive
oxygen species and proteolytic enzymes.
Antigenic targets of ANCA are intracellular (not accessible to circulating Abs);
ANCA antigens are constitutively expressed at low levels on the plasma
membrane or are translocated to cell surface in activated and apoptotic
leukocytes.
Mechanism for ANCA vasculitis:
o Drugs or cross-reactive microbial antigens induce ANCA formation;
alternatively, leukocyte surface expression or release of PR2 and MPO
(during infections) incites ANCA development in susceptible host.
o Subsequent infection, endotoxin exposure, or inflammatory stimulus
elicits cytokines (TNF) that upregulate surface expression of PR2 and
MPO on neutrophils and other cells.
o ANCAs bind these cytokine-activated cells, causing further activation of
neutrophils
o ANCA-activated neutrophils cause endothelial cell injuryrelease
granule contents and reactive oxygen species.
ANCA auto-Abs are directed against cellular constituents and do not form
circulating immune complexes.
o Vascular lesions do not contain demonstrable Ab and complement
pauci-immune
ANCAs directed against non-PR3/MPO proteins are seen in patients with non-
vasculitic inflammatory disorders, such as IBD, sclerosing cholangitis, and
rheumatoid arthritis.
Anti-Endothelial Cell Antibodies

Abs to endothelial cells, underlie certain vasculitides, such as Kawasaki

Disease.
Giant Cell (Temporal) Arteritis

Giant cell arteritis is the most common form of vasculitis among elderly in
developed countries.
Usually takes form of chronic, granulomatous, inflammation of large to small
size arteries, mainly those supplying the head (especially temporal arteries).
o Vertebral and ophthalmic arteries as well as the aorta (giant cell
aortitis) also can be involved.
 o Ophthalmic artery involvementsudden and permanent blindness;
affected must be diagnosed and treated promptly.
o Involves branches of carotid
Pathogenesis: T cell-mediated immune response to an uncharacterized vessel
wall antigen.
o Pro-inflammatory cytokines (TNF) and anti-endothelial cell antibodies
also contribute.
o Granulomatous infections, association with MHC class II haplotypes,
and therapeutic response to steroidsfavor immune etiology.
o The extraordinary predilection for temporal artery unexplained
vessels in various parts of body develop from distinct anlagen, and
may therefore express unique antigens.
Morphology:
o Pathological changes are patchy along length of affected vessels.
o Arterial segments involved exhibit nodular intimal thickening (and
occasional thromboses) that reduce lumen diameter and cause distal
ischemia.
o Classic lesionsgranulomatous inflammation within the inner media
centered on the internal elastic membrane
Infiltrate of lymphocytes and macrophages, with mutli-nucleate
giant cells, and fragmentation of the internal elastic lamina.
In 25%, granulomas and giant cells absent, and lesions exhibit
nonspecific pan-arteritis with a mixed infiltrate of acute and
chronic inflammation.
Healing marked by medial and adventitial fibrosis and intimal
thickening.

Clinical Features:
o Rare before 50 yearsolder white females
 o Signs, vague and constitutionalfever, fatigue, weight loss, facial
pain, h
Headache, most intense along superficial temporal artery
(painful to palpation).
Ocular symptoms associated with involvement of ophthalmic
artery, appear in 50%
Range from diplopia to complete vision loss.
Jaw claudication
o ESR often elevated
o Diagnosis depends on biopsy and histology
o Corticosteroid or anti-TNF therapies are effective.
Half of patients with temporal (giant cell) arteritis also have polymyalgia
rheumaticasyndrome of:
o (1) proximal muscle aches and stiffness
o (2) elevated erythrocyte sedimentation rate
o (3) rapid resolution of symptoms with low-dose corticosteroid
therapy

Takayasu Arteritis

Granulomatous vasculitis of medium-sized and larger arteries characterized

by ocular disturbances and marked weakening of pulses in upper extremities
(pulseless disease).
Manifests with transmural scarring and thickening of aortaparticularly the
aortic arch and great vesselswith severe luminal narrowing of the major
branch vessels.
Aortic lesions similar to giant cell aortitisdistinction made on basis of
patients age.
o Older than 50 yearsGCA
o Younger than 50 yearsTA
Global distribution, autoimmune etiology